Medical devices coated with porous carbon and methods of manufacturing the same

ABSTRACT

A method of creating a porous carbon coating on a medical device by applying a precursor carbon material on the medical device and then pyrolysing the precursor carbon material by laser irradiation. The laser irradiation may be focused to carbonize only certain portions of the medical device and any uncarbonized areas can be removed by solvent washing. Also provided is a medical device having a carbonized coating created according to the method of the present invention.

TECHNICAL FIELD

The present invention relates to porous carbon coatings on a medicaldevice and methods of manufacturing the same.

BACKGROUND

Many implantable medical devices have a coating in which the coating canperform various functions, such as improving the biocompatibility of thedevice or serving as a drug delivery system. Also, certain types ofporous coatings have been proposed to encourage the migration and normalgrowth of tissue onto the coating. This feature is beneficial in medicaldevices because it can enhance its effectiveness and reduce theincidence of unwanted effects and complications such as thrombosis,infection, scarring, or abnormal tissue growth.

One type of porous coating is a porous carbon coating, which has beendemonstrated to be highly biocompatible. Porous carbon coatings are ableto serve as localized drug delivery systems, which is beneficial inimproving the effectiveness of medical devices. Therapeutic agents canbe loaded into a porous carbon coating on a medical device and releasedinto the surrounding fluid or tissue after implantation.

There are various methods for creating a porous carbon coating on amedical device, including chemical vapor deposition, physical vapordeposition, and sputtering. Porous carbon can also be created bycarbonization in which a carbon-containing precursor material, such aswood, cellulose, coal, or synthetic polymer is pyrolysed. Duringpyrolysis, the carbon-containing precursor material decomposes, withmost of the non-carbon elements, such as hydrogen, nitrogen, and oxygenbeing removed in tarry or gaseous form. The resulting carbonization ofthe carbon-containing precursor material transforms it into a solidporous carbon mass.

U.S. Patent Publication No. 2005/0079200 (Rathenow et al.), whose entiredisclosure is incorporated by reference herein, describes porous carboncoatings on medical devices created by coating the medical device with apolymer film and then pyrolysing the polymer film by oven heating athigh temperatures. The oven heating method of Rathenow results in theuniform carbonization of all parts of the medical device coated with thepolymer film.

SUMMARY OF THE INVENTION

The present invention is directed to creating a non-uniform porouscarbon coating limited to certain portions of a medical device. In anembodiment, the present invention provides a method of creating a porouscarbon coating on a medical device by providing a medical device coatedwith a precursor carbon material, wherein the medical device has firstand second portions. The method further comprises heating the precursorcarbon material on at least the first portion of the medical device witha laser to form a carbonized layer. In other embodiments, the precursormaterial on both the first and the second portions of the medical deviceare heated with a laser, and wherein the porosity of the carbonizedlayer in the first portion is different from the porosity of thecarbonized layer in the second portion. In these embodiments, thediffering porosities are created by the use of additives in theprecursor carbon material, by various after-treatments to the carbonizedlayer, or by laser heating under different sets of heating conditions.

In certain embodiments, certain areas of the medical device may becooled by the use of streaming gas or fluid, or a cooling element. Anyuncarbonized precursor carbon material may be removed by variousmethods, including solvent washing. The methods of the present inventionmay further comprise the step of incorporating a therapeutic agent intothe carbonized porous carbon layer.

In another embodiment, the present invention provides a medical devicehaving a porous carbon coating on a portion of the medical device,wherein the portion is less than the entire surface of the medicaldevice, and wherein the porous carbon coating carries a therapeuticagent and provides for directionally controlled release of thetherapeutic agent. The porous carbon coating may be on the outerdiameter, inner diameter, or the side walls of a stent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of a bare, uncoated stent which can becoated according to the methods of the present invention.

FIG. 1B is a cross-sectional view of the stent of FIG. 1A taken at lineX-X.

FIG. 2 is a cross-sectional view of the stent of FIG. 1A with aprecursor carbon-containing material coated onto the stent.

FIG. 3 is a cross-sectional view of the stent of FIG. 2 with the portionof the coating on the outer diameter of the stent having beencarbonized.

FIG. 4 is a cross-sectional view of the stent of FIG. 3 with theuncarbonized material removed by solvent washing.

FIG. 5 is a cross-sectional view of a strut of a stent that is coatedaccording to the method of the present invention and implanted in ablood vessel.

DETAILED DESCRIPTION

Definitions: The term “porosity” as used herein refers to thecharacteristics of the pores, including the size, shape, dimensions,number, density, volume, ratio of the volume of all the pores in amaterial to the volume of the whole, structure, organization, andarchitecture of the pores, and whether the pores are closed or open. Theterm “directionally controlled release” as used herein refers to theability to release, discharge, or distribute a substance in certaindirections or into certain spaces. The term “precursor carbon material”as used herein refers to any carbon-based or carbon-containing materialwhich can become transformed into a solid porous carbon mass uponpyrolysis and/or carbonization.

The present invention provides methods of coating a medical device witha porous carbon coating and a medical device coated by such methods.Referring to FIGS. 1A and 1B, one example of a medical device that canbe coated according to the methods of the present invention is acoronary stent 10 having struts 12 and a central channel 16. While theexamples presented in the disclosure herein are for stents, the presentinvention can be applied to any medical device which can be coated.Referring to FIG. 2, precursor carbon-containing material is depositedonto the surfaces of the stent struts 12 to form a precursor coating 30.The precursor carbon material may be a polymer, including polymers thatare capable of forming vitreous carbon upon carbonization, such as thatare three-dimensionally cross-linked and have a high molecular weightand high degree of aromaticity. For example, polymers suitable for useas precursor materials include, but are not limited to, polyfurfurylalcohol, polyimide, polyvinyl alcohol, and cellulose. Other polymersthat could be used in the present invention include varnish-basedpolymer films such as those described in U.S. Patent Publication No.2005/0079200 (Rathenow et al.), which is incorporated by referenceherein.

The polymer may also be polymer foams such as phenolic foams, polyolefinfoams, polystyrene foams, polyurethane foams, fluoropolymer foams, orany other foam polymer which can be converted into porous carbon in asubsequent carbonizing step. In certain embodiments, foam polymers arepreferred because their carbonization results in porous carbon of thetype that is suitable for drug delivery.

The medical device may be coated with one or several polymer layers,partially or fully over the surface of the medical device. For a stent,the polymer coating should preferably be less than 20 μm thick. Theprecursor coating can be deposited by any of various methods, includingspraying, dipping, sheet shrinking, plating, sputtering, chemical orphysical vapor deposition, and the like, depending upon thecharacteristics of the coating material and the medical devicesubstrate.

The precursor coating material is then subjected to pyrolyticdecomposition under carbonization conditions to transform the coatinginto a carbonized layer. In the present invention, the precursor coatingmaterial is locally heated, for example, by laser irradiation using anyconventional laser, including CO₂ and Nd:YAG lasers. The laser may heatthe precursor coating material directly or indirectly by heat conductionthrough the body of the medical device. Whether the heating is direct orindirect can depend upon the type of laser used. For example, in apolymer coated metal stent, a CO₂ laser would preferably be absorbed bythe polymer coating, while a Nd:YAG laser would preferably be absorbedby the metal substrate. This preferential heating capability ofdifferent lasers may be used to select or limit the area ofcarbonization. For example, a CO2 laser can be used to heat the polymercoating while limiting heat conduction to portions of the polymercoating unexposed to the laser, such as the opposite face of the stentstruts. On the other hand, an Nd:YAG laser can be used to heat the metalsubstrate of the stent, thereby conducting heat to portions of thepolymer coating not directly exposed to the laser, such as the oppositeface of the stent struts.

The laser may heat the precursor coating material to a temperature inthe range of 200° C. to 2,500° C. to at least partially carbonize theprecursor material. In some cases, the temperature selected is thelowest temperature that will completely carbonize the polymer materialsthat may be used in the present invention. In such cases, generallyapplicable temperatures for the carbonization step range from 200° C. to1200° C., and in the case of certain embodiments, temperatures in therange of 250° C. to 700° C. may be used. One of skill in the art willunderstand that the rate, temperature, and duration of heating willinfluence the amount of carbonization and the porosity of the carbonizedlayer. Therefore, such factors can be varied to create a carbonizedlayer having the desired characteristics. For example, in a stent with apolymer coating of 10 μm thickness, heating at 300-500° C. for aduration of several seconds to one minute should be sufficient tocompletely carbonize the polymer.

The atmosphere during carbonization is essentially free of oxygen, withpreferably less than 10 ppm O₂, and even more preferably less than 1 ppmO₂. The carbonization can be performed in a vacuum, in a reducingatmosphere, or in an inert atmosphere, such as an atmosphere composed ofargon, neon, nitrogen, or any other inert gas or gas compounds that donot react with carbon. One of skill in the art will understand that thecomposition and pressure of the atmosphere will influence carbonization,and therefore, such factors can be adjusted to create a carbonized layerhaving the desired characteristics.

In an embodiment of the present invention, laser irradiation may be usedto carbonize all the precursor coating on the medical device. In otherembodiments, the laser can be directed in a pattern over the medicaldevice such that only portions of the precursor coating on the medicaldevice are heated. For example, referring to FIG. 3, the laser may befocused so that only a portion 32 of precursor coating 30 on the outerdiameter surface of stent struts 12 is carbonized. Alternatively, onlythe precursor coating on the inner diameter or on the side walls of thestent struts may be carbonized.

Localized carbonization may be further controlled by cooling certainareas of the medical device. Cooling can be accomplished by streaming acooling gas or fluid, or placing a cooling object onto or in proximityof the desired area of the medical device. For example, in oneembodiment, the precursor coating on the outer diameter of stent 10 maybe laser irradiated, while the surface of the inner diameter is cooledby a stream of gas being passed through the inside channel 16 of stent10. Alternatively, the precursor coating on the inner diameter of stent10 may be laser irradiated, while a cooling gas or fluid is streamedaround the outer diameter of stent 10. In another embodiment, theprecursor coating on the outer diameter may be laser irradiated, whilethe surface of the inner diameter is cooled by direct contact with orproximity to a cooling rod inserted through the channel 16 of the stent10. Alternatively, the precursor coating on the surface of the innerdiameter may be laser irradiated, while the surface of the outerdiameter is cooled by direct contact with or proximity to a hollowcooling cylinder surrounding the outer diameter of the stent 10.

With the appropriate selection of the precursor coating material and thecarbonization conditions, one of skill in the art could createcarbonized layers of various types and porosities. For example, usingfoam polymer as the precursor coating material would result in arelatively porous carbonized layer. Also, in certain embodiments of thepresent invention, the precursor coating material also includesadditives that enlarge the diameter of the pores or increase theporosity during carbonization. Examples of suitable additives includephosphoric acid, zinc chloride, H₂SO₄, K₂S, alkali metal hydroxide, andcarbonate and chlorides of Ca²⁺, Mg²⁺, and Fe³⁺. Other suitableadditives and a description of the use of such additives to influencecarbonization and modify the porosity of the carbonized layer aredescribed in U.S. Patent Publication No. 2005/0079200 (Rathenow et al.),which is incorporated by reference herein. Still more additives thatinfluence carbonization, such as binders and fillers, are described inU.S. Pat. No. 5,820,967 (Gadkaree), which is incorporated by referenceherein.

The carbonized layer can also be subjected to after-treatments such asoxidation, reduction, or incorporation of additives or fillers or othermaterials to further modify the porosity of the carbonized layer. Suchafter-treatments are described in Rathenow, which is incorporated byreference herein. For example, the hydrophilicity of the carbonizedlayer can be adjusted by the addition of inorganic nanoparticles intothe carbonized layer. In another example, the porosity of the carbonizedlayer can be modified by oxidation steps or by chemical vapor deposition(CVD) processes.

The precursor carbon material and carbonization conditions may beselected to create carbonized layers having porosity suitable forpromoting endothelial cell growth or migration. For example, theliterature indicates that pores sizes of 200 nm to 50 um can influenceendothelial cell growth.

In certain embodiments, different portions of the precursor coating canbe subjected to different carbonization conditions in order to createdifferent porosities in different portions of the resulting carbonizedlayer. In one embodiment, the rate, duration, and temperature of laserheating is varied in different portions of the precursor coating,resulting in different porosities in different portions of the resultingcarbonized layer. In another embodiment, different portions of theprecursor coating are subjected to different modifications or treatmentsdescribed above, resulting in different porosities in different portionsof the resulting carbonized layer. In still other embodiments, the aboveapproaches are combined to create different porosities in differentportions of the resulting carbonized layer.

For example, in a stent, a polymer foaming agent can be applied to theprecursor polymer coating on the inner diameter, while another additiveor no additive can be applied to the precursor polymer coating on theouter diameter of the stent. In another example, the precursor polymercoating on the inner diameter of the stent can be subjected to laserirradiation under one set of heating conditions, while the precursorpolymer coating on the outer diameter of the stent is subjected to laserirradiation under a different set of heating conditions.

After carbonization, the carbonized layer on the inner diameter of thestent would have porosity characteristics different from the carbonizedlayer on the outer diameter. Having on the inner diameter surface onetype of carbonized layer designed for endothelial cell growth, and onthe outer diameter surface another type of carbonized layer designed fordrug delivery, could improve the effectiveness of the stent.

Referring to FIG. 4, once the desired areas of the precursor coating arecarbonized, any uncarbonized precursor coating material can be removedfrom the medical device by chemical or physical means. Chemical removalcan be performed by washing or soaking the medical device in a solvent.The solvent may be any solvent that dissolves the uncarbonized precursorcoating material, including methanol, ethanol, N-propanol, isopropanol,butoxydiglycol, butoxyethanol, butoxyisopropanol, butoxypropanol,n-butyl alcohol, t-butyl alcohol, butylene glycol, butyl octanol,diethylene glycol, dimethoxydiglycol, dimethyl ether, dipropyleneglycol, ethoxydiglycol, ethoxyethanol, ethyl hexane diol, glycol, hexanediol, 1,2,6-hexane triol, hexyl alcohol, hexylene glycol, isobutoxypropanol, isopentyl diol, 3-methoxybutanol, methoxydiglycol,methoxyethanol, methoxyisopropanol, methoxymethylbutanol, methoxyPEG-10, methylal, methyl hexyl ether, methyl propane diol, neopentylglycol, PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, PEG-6-methyl ether, pentyleneglycol, PPG-7, PPG-2-buteth-3, PPG-2 butyl ether, PPG-3 butyl ether,PPG-2 methyl ether, PPG-3 methyl ether, PPG-2 propyl ether, propanediol, propylene glycol, propylene glycol butyl ether, propylene glycolpropyl ether, tetrahydrofuran, trimethyl hexanol, phenol, benzene,toluene, xylene; as well as water, if necessary in mixture withdispersants and mixtures of the above-named substances. In mechanicalremoval, physical movement of the medical device, such as ultrasonicvibration, flexing, or bending of the medical device can remove theuncarbonized precursor material.

The precursor carbon material and carbonization conditions may beselected to create carbonized layers having porosity suitable forbinding or carrying therapeutic agents within the pores and releasingthem in a controlled fashion. One of skill in the art can vary theporosity of the carbonized layer to control the release rate. Forexample, decreasing the sizes of the pores to smaller than 200 nm willslow the rate at which the therapeutic agents diffuse out of the pores.The therapeutic agent may also be combined with anypharmaceutically-acceptable excipient known in the art, such as thepolymers used in drug delivery, in order to further control the releaserate. Using an excipient to further control drug release may beadvantageous where the pores sizes are relatively large, such as poressizes greater than 500 nm.

Therapeutic agents may be added to the carbonized layer by any ofvarious methods including spray coating, roll coating, absorption,adsorption, vacuum impregnation, electrophoretic transfer, and the like.The manner in which the therapeutic agents are applied will depend uponthe characteristics of the carbonized layer, dimensions of the area tobe coated, and the type of therapeutic agent to be applied. For example,if the carbonized layer is limited to the outer diameter, roll coatingor spray coating can be used. If the carbonized area is small, inkjetmethods can be used. If the sizes of the pores are too small to allowefficient penetration of therapeutic agents, vacuum impregnation orelectrophoretic transfer may be suitable.

The method of the present invention can be used to make a medical devicehaving a porous carbon coating limited to certain portions on themedical device, wherein the porous carbon coating carries a therapeuticagent and provides for directionally controlled release of thetherapeutic agent. Thus, in a medical device having multiple surfaces oraspects, the porous carbon coating can be limited to certain surfaces oraspects in order to release the therapeutic agent with directionalcontrol. For example, FIG. 5 shows a stent strut 12 having a therapeuticagent-loaded porous carbon coating 32 limited to the outer surface 14(facing the vessel wall) of the stent strut 12. Therapeutic agentreleased (indicated by the arrows) from porous carbon coating 32 wouldbe distributed into the tunica media layer of the arterial wall,preferentially exposing the smooth muscle cells 20 to the therapeuticagent. Alternatively, the therapeutic agent-loaded porous carbon coatingmay be limited to the inner surface 18 (facing the lumen) of the stentstrut 12 so that the therapeutic agent would be distributed into thetunica intima layer of the arterial wall, preferentially exposing theendothelial cells 22 to the therapeutic agent. A stent having this typeof directionally controlled drug release would be beneficial inimproving the effectiveness of stent.

The medical device of the present invention is not limited to thecoronary stents in the disclosed embodiments. Non-limiting examples ofother medical devices that can be coated according to the methods of thepresent invention include catheters, guide wires, balloons, filters(e.g., vena cava filters), stents, stent grafts, vascular grafts,intraluminal paving systems, pacemakers, electrodes, leads,defibrillators, joint and bone implants, spinal implants, vascularaccess ports, intra-aortic balloon pumps, heart valves, sutures,artificial hearts, neurological stimulators, cochlear implants, retinalimplants, and other devices that can be used in connection withtherapeutic coatings. Such medical devices are implanted or otherwiseused in body structures or cavities such as the vasculature,gastrointestinal tract, abdomen, peritoneum, airways, esophagus,trachea, colon, rectum, biliary tract, urinary tract, prostate, brain,spine, lung, liver, heart, skeletal muscle, kidney, bladder, intestines,stomach, pancreas, ovary, uterus, cartilage, eye, bone, and the like.

Such medical devices may be made of any type of material in whichimplanted medical devices are generally made, including amorphous and/or(partially) crystalline carbon, complete carbon material, porous carbon,graphite, composite carbon materials, carbon fibres, ceramics such ase.g. zeolites, silicates, aluminium oxides, aluminosilicates, siliconcarbide, silicon nitride; metal carbides, metal oxides, metal nitrides,metal carbonitrides, metal oxycarbides, metal oxynitrides and metaloxycarbonitrides of the transition metals such as titanium, zirconium,hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten,manganese, rhenium, iron, cobalt, nickel; metals and metal alloys, inparticular the noble metals gold, silver, ruthenium, rhodium, palladium,osmium, iridium, platinum; metals and metal alloys of titanium, zircon,hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten,manganese, rhenium, iron, cobalt, nickel, copper; steel, in particularstainless steel, shape memory alloys such as nitinol, nickel-titaniumalloys, glass, stone, glass fibres, minerals, natural or synthetic bonesubstance bone, imitates based on alkaline earth metal carbonates suchas calcium carbonate, magnesium carbonate, strontium carbonate and anydesired combinations of the above-mentioned materials.

The precursor carbon-containing material can be a polymer such ashomopolymers or copolymers of aliphatic or aromatic polyolefins such aspolyethylene, polypropylene, polybutene, polyisobutene, polypentene;polybutadiene; polyvinyls such as polyvinyl chloride or polyvinylalcohol, poly(meth)acrylic acid, polyacrylocyano acrylate;polyacrylonitril, polyamide, polyester, polyurethane, polystyrene,polytetrafluoroethylene; polymers such as collagen, albumin, gelatine,hyaluronic acid, starch, celluloses such as methylcellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose,carboxymethylcellulose phthalate; waxes, paraffin waxes, Fischer-Tropschwaxes; casein, dextrans, polysaccharides, fibrinogen,poly(D,L-lactides), poly(D,L-lactide coglycolides), polyglycolides,polyhydroxybutylates, polyalkyl carbonates, polyorthoesters, polyesters,polyhydroxyvaleric acid, polydioxanones, polyethylene terephthalates,polymaleate acid, polytartronic acid, polyanhydrides, polyphosphazenes,polyamino acids; polyethylene vinyl acetate, silicones; poly(esterurethanes), poly(ether urethanes), poly(ester ureas), polyethers such aspolyethylene oxide, polypropylene oxide, pluronics, polytetramethyleneglycol; polyvinylpyrrolidone, poly(vinyl acetate phthalate) as well astheir copolymers, mixtures and combinations of these homopolymers orcopolymers.

The therapeutic agent in a coating of a medical device of the presentinvention may be any pharmaceutically acceptable agent such as anon-genetic therapeutic agent, a biomolecule, a small molecule, orcells.

Exemplary non-genetic therapeutic agents include anti-thrombogenicagents such heparin, heparin derivatives, prostaglandin (includingmicellar prostaglandin E1), urokinase, and PPack (dextrophenylalanineproline arginine chloromethylketone); anti-proliferative agents such asenoxaparin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus,zotarolimus, monoclonal antibodies capable of blocking smooth musclecell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatoryagents such as dexamethasone, rosiglitazone, prednisolone,corticosterone, budesonide, estrogen, estrodiol, sulfasalazine,acetylsalicylic acid, mycophenolic acid, and mesalamine;anti-neoplastic/anti-proliferative/anti-mitotic agents such aspaclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate,doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine,vincristine, epothilones, endostatin, trapidil, halofuginone, andangiostatin; anti-cancer agents such as antisense inhibitors of c-myconcogene; anti-microbial agents such as triclosan, cephalosporins,aminoglycosides, nitrofurantoin, silver ions, compounds, or salts;biofilm synthesis inhibitors such as non-steroidal anti-inflammatoryagents and chelating agents such as ethylenediaminetetraacetic acid,O,O′-bis(2-aminoethyl) ethyleneglycol-N,N,N′,N′-tetraacetic acid andmixtures thereof; antibiotics such as gentamycin, rifampin, minocyclin,and ciprofloxacin; antibodies including chimeric antibodies and antibodyfragments; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; nitric oxide; nitric oxide (NO) donors such as linsidomine,molsidomine, L-arginine, NO-carbohydrate adducts, polymeric oroligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Argchloromethyl ketone, an RGD peptide-containing compound, heparin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, enoxaparin, hirudin,warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, plateletaggregation inhibitors such as cilostazol and tick antiplatelet factors;vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promoters; vascular cell growth inhibitorssuch as growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin; cholesterol-lowering agents; vasodilating agents; agentswhich interfere with endogenous vasoactive mechanisms; inhibitors ofheat shock proteins such as geldanamycin; angiotensin converting enzyme(ACE) inhibitors; beta-blockers; βAR kinase (βARK) inhibitors;phospholamban inhibitors; protein-bound particle drugs such asABRAXANE™; and any combinations and prodrugs of the above.

Exemplary biomolecules include peptides, polypeptides and proteins;oligonucleotides; nucleic acids such as double or single stranded DNA(including naked and cDNA), RNA, antisense nucleic acids such asantisense DNA and RNA, small interfering RNA (siRNA), and ribozymes;genes; carbohydrates; angiogenic factors including growth factors; cellcycle inhibitors; and anti-restenosis agents. Nucleic acids may beincorporated into delivery systems such as, for example, vectors(including viral vectors), plasmids or liposomes.

Non-limiting examples of proteins include serca-2 protein, monocytechemoattractant proteins (MCP-1) and bone morphogenic proteins (“BMPs”),such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VGR-1), BMP-7(OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15.Preferred BMPs are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7.These BMPs can be provided as homodimers, heterodimers, or combinationsthereof, alone or together with other molecules. Alternatively, or inaddition, molecules capable of inducing an upstream or downstream effectof a BMP can be provided. Such molecules include any of the “hedgehog”proteins, or the DNA's encoding them. Non-limiting examples of genesinclude survival genes that protect against cell death, such asanti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; andcombinations thereof. Non-limiting examples of angiogenic factorsinclude acidic and basic fibroblast growth factors, vascular endothelialgrowth factor, epidermal growth factor, transforming growth factors αand β, platelet-derived endothelial growth factor, platelet-derivedgrowth factor, tumor necrosis factor α, hepatocyte growth factor, andinsulin-like growth factor. A non-limiting example of a cell cycleinhibitor is a cathespin D (CD) inhibitor. Non-limiting examples ofanti-restenosis agents include p15, p16, p18, p19, p21, p2′7, p53, p57,Rb, nFkB and E2F decoys, thymidine kinase and combinations thereof andother agents useful for interfering with cell proliferation.

Exemplary small molecules include hormones, nucleotides, amino acids,sugars, and lipids and compounds have a molecular weight of less than100 kD.

Exemplary cells include stem cells, progenitor cells, endothelial cells,adult cardiomyocytes, and smooth muscle cells. Cells can be of humanorigin (autologous or allogenic) or from an animal source (xenogenic),or genetically engineered. Non-limiting examples of cells include sidepopulation (SP) cells, lineage negative (Lin⁻) cells including Lin⁻CD34⁻, Lin⁻CD34⁺, Lin⁻cKit⁺, mesenchymal stem cells includingmesenchymal stem cells with 5-aza, cord blood cells, cardiac or othertissue derived stem cells, whole bone marrow, bone marrow mononuclearcells, endothelial progenitor cells, skeletal myoblasts or satellitecells, muscle derived cells, go cells, endothelial cells, adultcardiomyocytes, fibroblasts, smooth muscle cells, adult cardiacfibroblasts +5-aza, genetically modified cells, tissue engineeredgrafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones,embryonic stem cells, fetal or neonatal cells, immunologically maskedcells, and teratoma derived cells.

Any of the therapeutic agents may be combined to the extent suchcombination is biologically compatible.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Each ofthe disclosed aspects and embodiments of the present invention may beconsidered individually or in combination with other aspects,embodiments, and variations of the invention. In addition, unlessotherwise specified, none of the steps of the methods of the presentinvention are confined to any particular order of performance.Modifications of the disclosed embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art andsuch modifications are within the scope of the present invention.Furthermore, all references cited herein are incorporated by referencein their entirety.

1. A medical device with a porous carbon coating on a portion of themedical device, wherein the portion is less than the entire surface ofthe medical device, and wherein the porous carbon coating carries atherapeutic agent and provides for directionally controlled release ofthe therapeutic agent.
 2. The medical device of claim 1, wherein themedical device is a stent.
 3. The medical device of claim 2, wherein theportion is the outer diameter surface of the stent.
 4. The medicaldevice of claim 2, wherein the portion is the inner diameter surface ofthe stent.
 5. The medical device of claim 2, wherein the porous carboncoating is only on the outer diameter surface, only on the innerdiameter surface, or only on the sidewalls of the stent.
 6. The medicaldevice of claim 5, wherein the porous carbon coating is only on theouter diameter surface of the stent.
 7. The medical device of claim 5,wherein the porous carbon coating is only on the inner diameter surfaceof the stent.
 8. The medical device of claim 5, wherein the porouscarbon coating is only on the sidewalls of the stent.
 9. The medicaldevice of claim 2, wherein the porosity of the porous carbon coating ata first site on the stent is different from the porosity at a secondsite on the stent.